ABSTRACT Vascular SMCs are specialized cells that express a contractile, quiescent phenotype, but are capable of undergoing significant phenotypic and functional alterations. As a result, mature SMCs are major contributors to pathological vascular remodeling. Using a highly specific SMC lineage-mapping approach, remarkably, we detected SMC-derived cells in the arterial adventitia, suggesting that mature SMCs contribute to both intimal and adventitial remodeling. The recent discovery that the normal adventitia is home to a resident population of vascular stem/progenitor cells with multiple fate potentials raised new and important questions about roles these cells play in growth, remodeling, repair, and disease of the artery wall. We described a population of adventitial vascular progenitor cells that express the progenitor cell markers Sca1 and CD34 (AdvSca1 cells) and cluster in an adventitial domain of hedgehog signaling. Our published work demonstrated two distinct subpopulations of AdvSca1 cells, one that derives from mature SMCs that undergo reprogramming in situ and is dependent on induction of the transcription factor, Klf4. Other groups have shown that induction of Klf4 in SMCs promotes SMC cell transitions in the setting in atherosclerosis and cancer progression, however the mechanism underlying Klf4 induction remains unknown. We also demonstrated that SMC-derived AdvSca1 cells (AdvSca1-SM) exhibit a multipotent phenotype capable of differentiating into multiple cell types. Further, we demonstrated that AdvSca1- SM cells expand rapidly in response to vascular injury suggesting that these cells are the dominant source of injury-induced adventitial remodeling. The full functional capacity of AdvSca1-SM cells in the setting of vascular disease remains unknown largely due to the lack of a reliable and specific lineage-mapping system. Our new data support the concept that the adventitial microenvironment is critical to the reprogramming process and promotes reprogramming through induction of constitutive Gli1 activity, which induces the long non-coding RNA (lncRNA) H19, and downstream activation of Wnt/?-catenin signaling. Wnt/?-catenin activity drives expression of the pluripotency genes, Myc and Klf4, resulting in SMC reprogramming and AdvSca1-SM cell maintenance and quiescence. In response to injury, AdvSca1-SM cells downregulate Gli1/H19/Wnt/?-catenin/Klf4 signaling, acquire a pro-fibrotic myofibroblast phenotype, and are the major contributors to vascular fibrosis. In contrast, mature SMCs downregulate SMC markers and acquire a progenitor cell phenotype. For this project, we propose that the unique adventitial microenvironment promotes SMC reprogramming by autonomous and constitutive activation of Gli1/H19/Wnt/?-catenin signaling (Aim One), that loss of Gli1/H19/Wnt/?-catenin activity promotes AdvSca1-SM-to-myofibroblast differentiation and adventitial fibrosis in the setting of injury or vasa vasorum expansion and plaque neovascularization in the setting of atherogenesis (Aim Two), and that the atherosclerotic plaque microenvironment promotes SMC reprogramming through a similar pathway to contribute to intimal SMC and macrophage accumulation (Aim Three).